Much higher doses of docosahexaenoic acid (DHA) than initially thought may be required to effectively fight Alzheimer’s disease (AD), new research suggests.
In results that could explain why the omega-3 fatty acid has failed to prevent AD or slow its progression, investigators found that among individuals who took omega-3 supplements, DHA blood plasma levels were high, but cerebrospinal fluid (CSF) levels were relatively low.
“Despite the fact that we gave a relatively large dose of DHA, we only saw a modest increase in CSF DHA levels,” senior author Hussein Yassine, MD, associate professor of medicine and neurology at the Keck School of Medicine, University of Southern California, Los Angeles, California, told Medscape Medical News. “So the blood levels don’t reflect the increase in the brain.”
In a second key study finding, the researchers found that among individuals with the apolipoprotein E4 (APOE4) gene variant, the increase in serum DHA levels after supplementation was even lower.
“This suggests that there is some dysregulation process, where APOE4 carriers require either high doses or longer duration of supplementation to offset this effect,” Yassine added.
The study was published online July 17 in EBioMedicine.
Previous research has suggested a link between greater consumption of DHA omega-3 fatty acids and a lower risk for AD. Conversely, lower blood serum DHA levels have been associated with the accumulation of amyloid plaques in the brain, lower cognitive function, and smaller hippocampal volumes.
However, previous clinical trials that evaluated omega-3s for AD prevention or for slowing cognitive decline in AD patients showed little benefit.
Furthermore, a recent systematic review concluded that trials that used supplements with lower DHA doses (<1 g/d) for the primary prevention of AD had no cognitive benefit for healthy older people.
These disappointing findings may be because previous studies of the use of DHA supplements for the prevention of AD were built on the assumption that omega-3 fatty acid easily and rapidly crosses the blood-brain barrier.
The researchers hypothesized that larger doses of DHA are required for adequate brain bioavailability. They also theorized that the APOE4 gene variant is associated with reduced delivery of both DHA and eicosapentaenoic acid (EPA) to the brain before the onset of cognitive impairment.
To test their hypotheses, the investigators conducted a randomized placebo-controlled pilot study that included 33 individuals, all of whom had AD risk factors but were without cognitive impairment.
All of the participants had a family history of AD, lived a sedentary lifestyle, and consumed a diet low in fatty fish. Fifteen participants were carriers of the APOE4 gene variant. Of these individuals, seven were in the placebo group, and eight were in the intervention group. The remaining 18 participants were noncarriers.
All participants received daily vitamin B complex (1 mg vitamin B12; 100 mg vitamin B6; 800 μg folic acid), which helps the body process omega-3s. Participants were then randomly assigned to receive either DHA 2152 mg/d or placebo for 6 months.
Twenty-six participants underwent lumbar puncture and MRI, and 29 completed cognitive assessments at baseline and at 6 months.
Notably, the DHA dose in the current study far exceeds those that were previously used in major clinical trials testing the preventive power of omega-3s in AD. In these studies, the typical dose was 1 g/d or less.
The study’s primary endpoint was the change in DHA levels in the CSF. Secondary outcomes included changes in EPA levels in the CSF, as well as hippocampal volume and entorhinal thickness, as determined by MRI. Participants also underwent a series of tests to assess cognition.
Results showed that among participants in the DHA supplement group (n = 13), blood plasma DHA levels were 200% higher than for patients in the placebo group (n = 13). In contrast, CSF levels were only 28% higher in the intervention group vs the placebo group (mean difference, 0.08 μg/mL; P < .0001).
The researchers also found that among carriers of the APOE4 mutation in the active intervention group, DHA levels in CSF were lower, despite the fact that these patients received the same dose as noncarriers (mean difference, 0.02 μg/mL; P = .08).
Similarly, there was a 43% increase in CSF EPA levels in the patients in the active intervention arm compared with patients in the placebo arm (mean difference, 0.008 μg/mL; P < .0001). The increase in CSF EPA in non-APOE4 carriers after supplementation was three times greater than in APOE4 carriers (mean difference, 0.006 μg/mL; P = .001).
“E4 carriers, despite having the same dose, had less omega-3s in the brain. This finding suggests that EPA is either getting consumed, getting lost, or not getting absorbed into the brain as efficiently with the E4 gene,” Yassine said in a release.
There were no significant differences were between study groups with respect to changes in hippocampal volume (–0.002; P = .56) or entorhinal cortex thickness (–0.11; P = .13). Measures of cognition were statistically comparable between treatment arms in all but one measure, which favored the active intervention group.
The study’s findings suggest that blood testing does not accurately reflect how much DHA is reaching the brain, the investigators note. They conclude that in AD prevention studies testing omega-3 supplementation doses ≤1 g/d, brain effects may be reduced, particularly for APOE4 carriers.
“Since this was a pilot study, we can’t make broad conclusions that apply to large groups of patients. To give omega-3s a chance and definitively say whether they can be used to prevent Alzheimer’s disease or not, we also need to use much larger doses than we have in past studies,” said Yassine.
“We will also need a concerted effort to bring in a large group of individuals at risk of this disease to figure this out. Performing small studies with lower doses is going to keep giving us mixed messages,” he added.
Yassine’s team has secured funding for a larger trial. They are currently recruiting for the study, which will follow 320 participants for 2 years and will examine whether higher DHA doses can slow cognitive decline in APOE4 carriers.
Commenting on the findings for Medscape Medical News, Melanie Plourde, PhD, from Université De Sherbrooke, Sherbrooke, Canada, who was not involved in the study, said the beneficial effects of DHA supplementation are mediated by individuals’ vitamin B status.
“There is some recent evidence showing that if you provide omega-3 supplementation, there is no benefit on cognition if the vitamin B status is inadequate,” said Plourde. “The vitamin B makes it possible to generate more DHA into a form the brain can utilize.”
Plourde was skeptical about the need for a 2-g dose of supplemental DHA.
“If you provide 2 g of DHA as triglycerides, I think it’s fairly useless, because it doesn’t target the brain,” she said. “But you might get the same results with a much lower dose if you provide the omega-3s in a specific formulation that better targets the brain.”
She also noted that a 2-g dose of DHA can cause gastrointestinal upset in some individuals. “So there might be a lot of people who are not compliant with treatment. It’s not for everybody.”
The study was supported by the National Institute of Aging, the Alzheimer’s Association, and the National Institutes of Health. Yassine and Plourde have disclosed no relevant financial relationships.
EBioMedicine. Published online July 17, 2020. Full text